Myeloperoxidase, paraoxonase-1, and HDL form a functional ternary complex

Abstract

Myeloperoxidase (MPO) and paraoxonase 1 (PON1) are high-density lipoprotein-associated (HDL-associated) proteins mechanistically linked to inflammation, oxidant stress, and atherosclerosis. MPO is a source of ROS during inflammation and can oxidize apolipoprotein A1 (APOA1) of HDL, impairing its atheroprotective functions. In contrast, PON1 fosters systemic antioxidant effects and promotes some of the atheroprotective properties attributed to HDL. Here, we demonstrate that MPO, PON1, and HDL bind to one another, forming a ternary complex, wherein PON1 partially inhibits MPO activity, while MPO inactivates PON1. MPO oxidizes PON1 on tyrosine 71 (Tyr 71 ), a modified residue found in human atheroma that is critical for HDL binding and PON1 function. Acute inflammation model studies with transgenic and knockout mice for either PON1 or MPO confirmed that MPO and PON1 reciprocally modulate each other's function in vivo. Further structure and function studies identified critical contact sites between APOA1 within HDL, PON1, and MPO, and proteomics studies of HDL recovered from acute coronary syndrome (ACS) subjects revealed enhanced chlorotyrosine content, site-specific PON1 methionine oxidation, and reduced PON1 activity. HDL thus serves as a scaffold upon which MPO and PON1 interact during inflammation, whereupon PON1 binding partially inhibits MPO activity, and MPO promotes site-specific oxidative modification and impairment of PON1 and APOA1 function.

Dysfunctional HDL: From Structure-Function-Relationships to Biomarkers

“…The interpretation of PON1 activity is difficult because it is not known to which extent the paraoxonase and arylesterase activities represent biologically relevant functions. Furthermore, we and others observed important posttranslational modifications of the proteins, which could explain alterations of biological properties of the enzymes (Aviram et al 1999;Besler et al 2011;Huang et al 2013). …”

“…Studies investigating the lipidome of HDL are still somewhat limited by the available technologies. Importantly, several studies have associated changes in specific HDL protein either due to altered composition or modification to the loss of function of HDL (Besler et al 2011;Huang et al 2013;Shao et al 2006Shao et al , 2012Zheng et al 2004). Nevertheless, it remains to be determined if the alterations are secondary to changes that occur during the disease progression or if the alteration has indeed a causal effect on disease etiology.…”

HDL subfraction distribution and HDL function in untreated dyslipidemic patients

“…Interestingly, some previous studies proved that PON1 is predominantly associated to the smaller and denser HDL3 subfractions, and PON1 activity of HDL2 was only 4% of that in HDL3 [10] . Furthermore, previous data indicate that MPO, PON1 and HDL from a functional ternary complex in which MPO and PON1 inhibit each other's activity demonstrating the dysfunction of the HDL particle [11] . Dyslipidemia character ized by high levels of tr iglyc er ide, tot al and LD L c holesterol is an established risk factor for coronary heart disease.…”

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

“…146 PON1 inhibited MPO peroxidase activity, whereas in parallel site-specific oxidative modification of PON1 by MPO impaired PON1 function. 146 Recent studies linked the loss of endothelial HDL functionality in CAD and ACS patients to the increased content of the lipid peroxidation product malondialdehyde (MDA) in HDL due to reduced PON1 activity. 40 HDL-mediated nitric oxide production in endothelial cells was found impaired in patients with either stable CAD or ACS.…”